Risperidone (also known as 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one and marketed under the trade name RISPERDAL®) is an atypical antipsychotic medication. The chemical structure of risperidone is shown in formula (I).

Risperidone is most often used to treat delusional psychosis (including schizophrenia), also risperidone finds utility in treatment of some forms of bipolar disorder, psychotic depression, obsessive-compulsion disorder, and Tourette syndrome. Risperidone is also used in low doses for treating autistic spectrum disorders. Risperidone's therapeutic activity in schizophrenia is believed to be mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor antagonism.
Currently, Risperidone is available as immediate release tablets/syrups as well as long acting injectable. Long acting injections has gained acceptance with the medical fraternity owing to decreased incidences of hospitalization in patients with schizophrenia. The commercial sustained release product of an atypical psychotic is Risperdal® Consta, marketed by Janssen. Risperdal® consta is an intramuscular microsphere formulation and is intended to deliver therapeutic levels of risperidone for two weeks. However due to inherent lag phase of microsphere product, the patient is required to supplement the first 21 days of Risperdal® consta treatment with daily doses of risperidone by oral therapy. Approximately three weeks after a single intramuscular injection of Risperdal® consta and concurrent daily doses of oral risperidone, the microparticles release sufficient risperidone in the systemic circulation so that the patient can discontinue supplementation with daily doses of oral therapy.
The primary limitation of micro spheres used in sustained-release delivery systems is, typically the limited amount of drug that can be entrapped in the dosage form with complex manufacturing process & controls & high costs. Further, the size of the gauze of injection needle is limited by the discomfort of the patient.
Other sustained-release delivery systems such as solid, biodegradable rods or nondegradable reservoir typically require surgical implantation. Furthermore, for the non-degradable delivery systems, a second surgical procedure is required to remove the empty reservoir.
The afore-mentioned delivery systems require use of expensive excipients, special device and need specifically designed processes. Hence making them very expensive and increase cost of therapy.
EP-0,196,132 discloses the compound 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, that is known generally as risperidone and is a potent antipsychotic. The same patent also discloses the acid addition salt of risperidone for example, inorganic acids, such as hydrohalic acid, e.g. hydrochloric, hydrobromic and the like, and sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.
U.S. Pat. No. 5,612,346 disclose the pamoate acid addition salt of Risperidone having melting point of 269.2° C. and a process for the preparation thereof. The '346 patent also discloses a long acting pharmaceutical formulation of pamoate salt of risperidone. The poorly soluble salt form is suspended in the aqueous vehicle and was shown effective for over 2 week period in dogs. However, this product is not available in clinic. Olanzapine Pamoate (Zyprexa Relprevv) is available as long acting injectable formulation given IM for human use for the treatment of atypical antipsychotic disorders, is another example where poorly soluble salt form is suspended in aqueous vehicle. There is no lag phase observed in this kind of system and thus oral supplement are not required after first depot administration unlike the current marketed preparation Risperdal® consta.
WO 2004094414 discloses water soluble salt of risperidone in solid state having a water solubility of at least 10 mg/ml. The salt preferably has solubility within the range of 20 to 200 mg/ml. The salt is preferably a pharmaceutically acceptable acid addition salt include hydrochloric acid, methane sulfonic acid, tartaric acid, maleic acid, malic acid, ethane disulfonic acid, lactic acid, acetic acid, and mandelic acid.
Risperidone acid addition salts known in art are either not suitable for long acting formulation because of their physical characteristics or requires high drug loading due to their high molecular weight to achieve desirable drug concentration for long lasting effect.
There still exists need for acid addition salt of risperidone that has desired physical characteristics that are distinct from the previously disclosed and prepared salt of risperidone.
The discovery of new salt forms of a pharmaceutically useful compound risperidone provides a new opportunity to design drug delivery systems with improved pharmacokinetic profile with constant plasma concentrations with minimum peak & trough ratio, improved safety profile, ranging from few days to months. The salts would be useful for designing drug delivery system from immediate release to long acting dosage forms by different routes of administration
We have now surprisingly and unexpectedly discovered novel acid addition salts of risperidone, which are different from the known salt of risperidone disclosed in said prior art.